Dextromethorphan extended release pharmaceutical composition

Abstract

The invention is directed to pharmaceutical compositions comprising dextromethorphan and methods of use thereof. Formulations of the present invention include dextromethorphan or a pharmaceutically acceptable salt thereof in a sustained release formulation comprising a controlled release agent. Formulations of the present invention include a core tablet, optionally an active coating and, optionally a film coating. The pharmaceutical compositions may be used as an antitussive, and the invention further relates to the treatment of cough in a patient in need thereof.

What is claimed is: 
     
       1. A sustained release pharmaceutical tablet composition comprising:
 a) a core tablet sustained release formulation comprising
 i. dextromethorphan HBr in an amount selected from about 12.50%, 17.44%, 18.40%, 23.26%, 23.28%, 23.37%, 23.50%, 23.83%, 25.00%, 25.75%, 26.02%, 26.67%, and 28.17% by weight of the composition; 
 ii. hydroxypropyl methylcellulose having an apparent viscosity of from about 2,663 to about 4,970 mPa·s at 2 wt % in water, a methyl substitution between about 22.0% and 24.0%, and a hydroxypropyl substitution between about 7.5% and 9.5%, in an amount selected from the group consisting of about 8.33%, 8.58%, 8.89%, 9.12%, 9.13%, 9.17%, 9.22%, 9.29%, 9.39%, 9.52%, 12.27%, 14.08%, 15.89%, 16.67%, 17.17%, 17.44%, 17.78%, 18.40%, 18.78%, 22.39%, 25.00%, 27.50%, 33.33%, and 33.91% by weight of the composition; 
 iii. hydroxypropyl methylcellulose having an apparent viscosity of from about 13,275 to about 24,780 mPa·s, a methyl substitution between about 22.0% and 24.0%, and a hydroxypropyl substitution between about 8.5% and 10.5%, in an amount selected from the group consisting of about 8.33%, 9.12%, 9.13%, 9.17%, 9.29%, 9.39%, 9.52%, 12.22%, 12.50%, 12.88%, 13.33%, 14.08%, 15.67%, 15.89%, 16.67%, 17.17%, 17.44%, 17.78%, 18.40%, 18.78%, and 23.01% by weight of the composition; 
 iv. lactose monohydrate in an amount selected from about 14.89%, 17.24%, 17.30%, 17.82%, 18.45%, 19.49%, 19.60%, 22.25%, 22.64%, 23.25%, 23.55%, 23.75%, 23.76%, 24.00%, 24.67%, 25.02%, 25.41%, 25.87%, 26.23%, 26.32%, 27.73%, 27.80%, 29.73%, 29.74%, 29.86%, 29.99%, 30.28%, 30.60%, and 40.67% by weight of the composition; 
 v. microcrystalline cellulose in an amount selected from about 0%, 13.53%, 15.46%, 15.89%, 16.67%, 17.22%, 17.39%, 18.14%, 18.22%, 19.24%, 19.31%, 19.60%, 20.21%, 20.34%, 20.65%, 20.67%, 20.75%, 20.84%, 20.95%, 21.04%, 21.26%, 21.70%, 23.25%, 23.61%, 25.47%, 26.23%, 26.59%, and 30.37% by weight of the composition; 
 vi. fumed silica in an amount selected from about 0.33%, 0.35%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, or 0.50% by weight of the composition; and 
 vii. magnesium stearate in an amount selected from about 0.35%, 0.49%, 0.50%, 0.67%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, and 0.75% by weight of the composition; 
 b) optionally, an active coating comprising: 
 i. dextromethorphan or a pharmaceutically acceptable salt thereof in an amount selected from about 1.86%, 4.11%, 4.12%, 4.15%, and 4.21% by weight of the composition; 
 ii. hydroxypropyl methylcellulose having an apparent viscosity range of about 2.4-7 mPa·s at 2 wt % in water, a methyl substitution range of about 28.0%-30.0%, and a hydroxypropyl substitution range of about 7.0%-12.0% in an amount selected from about 0%, 0.41%, 0.47%, and 0.91% by weight of the composition; 
 iii. polyvinyl pyrrolidone in an amount selected from about 0%, 0.41%, 0.91%, 1.37%, and 1.38% by weight of the composition; 
 iv. sodium lauryl sulfate in an amount selected from about 0%, 0.004%, 0.01%, and 0.06% by weight of the composition; 
 v. PEG 400 or PEG 8000 in an amount selected from about 0%, 0.20%, and 0.46% by weight of the composition; 
 and c) the film coating is absent or comprises a polymer and a plasticizer; 
 
 wherein the tablet has a volume of from about 0.0063 in 3  to about 0.0183 in 3 , a surface area of from about 0.194 in 2  to about 0.395 in 2 , and a surface area to volume ratio of from about 19.4 in −1  to about 31.0 in −1 . 
 
     
     
       2. The sustained release pharmaceutical tablet composition of  claim 1 , wherein
 a) the core tablet sustained release formulation comprises
 i. about 23.28% of dextromethorphan HBr by weight of the composition; 
 ii. about 9.13% of hydroxypropyl methylcellulose having an apparent viscosity of from about 2,663 to about 4,970 mPa·s at 2 wt % in water, a methyl substitution between about 22.0% and 24.0%, and a hydroxypropyl substitution between about 7.5% and 9.5%, by weight of the composition; 
 iii. about 9.13% of hydroxypropyl methylcellulose having an apparent viscosity of from about 13,275 to about 24,780 mPa·s, a methyl substitution between about 22.0% and 24.0%, and a hydroxypropyl substitution between about 8.5% and 10.5%, by weight of the composition; 
 iv. about 29.74% of lactose monohydrate by weight of the composition; 
 v. about 20.67% microcrystalline cellulose by weight of the composition; 
 vi. about 0.47% fumed silica by weight of the composition; and 
 vii. about 0.70% magnesium stearate by weight of the composition; 
 
 b) the active coating is present and comprises
 i. about 4.11% dextromethorphan HBr by weight of the composition; 
 ii. about 0.91% polyvinylpyrrolidone by weight of the composition; 
 iii. about 0.91% of hydroxypropyl methylcellulose having an apparent viscosity range of 2.4-3.6 mPa·s, a methyl substitution of 28.0%-30.0% (inclusive), and a hydroxypropyl substitution of 7.0%-12.0% (inclusive) by weight of the composition; 
 iv. about 0.46% of polyethylene glycol by weight of the composition; and 
 v. about 0.01% of sodium lauryl sulfate by weight of the composition; and 
 
 c) the film coating is present and comprises a polymer, plasticizer and pigment. 
 
     
     
       3. The pharmaceutical composition of  claim 2 , comprising a film coating in an amount of about 0.50% by weight of the composition, wherein the film coating comprises hypromellose, polyethylene glycol, and optionally, one or more of polydextrose, talc, a pigment, and titanium dioxide. 
     
     
       4. The sustained release pharmaceutical tablet composition of  claim 1 , wherein
 a) the core tablet sustained release formulation comprises
 i. about 25.00% of dextromethorphan HBr by weight of the composition; 
 ii. about 8.33% of hydroxypropyl methylcellulose having an apparent viscosity of from about 2,663 to about 4,970 mPa·s at 2 wt % in water, a methyl substitution between about 22.0% and 24.0%, and a hydroxypropyl substitution between about 7.5% and 9.5%, by weight of the composition; 
 iii. about 12.50% of hydroxypropyl methylcellulose having an apparent viscosity of from about 13,275 to about 24,780 mPa·s, a methyl substitution between about 22.0% and 24.0%, and a hydroxypropyl substitution between about 8.5% and 10.5%, by weight of the composition; 
 iv. about 24.67% of lactose monohydrate by weight of the composition; 
 v. about 25.47% microcrystalline cellulose by weight of the composition; 
 vi. about 0.45% fumed silica by weight of the composition; and 
 vii. about 0.67% magnesium stearate by weight of the composition; 
 
 or, 
 the core tablet sustained release formulation comprises
 i. about 25.00% of dextromethorphan HBr by weight of the composition; 
 ii. about 16.67% of hydroxypropyl methylcellulose having an apparent viscosity of from about 2,663 to about 4,970 mPa·s at 2 wt % in water, a methyl substitution between about 22.0% and 24.0%, and a hydroxypropyl substitution between about 7.5% and 9.5%, by weight of the composition; 
 iii. about 16.67% of hydroxypropyl methylcellulose having an apparent viscosity of from about 13,275 to about 24,780 mPa·s, a methyl substitution between about 22.0% and 24.0%, and a hydroxypropyl substitution between about 8.5% and 10.5%, by weight of the composition; 
 iv. about 17.30% of lactose monohydrate by weight of the composition; 
 v. about 20.34% microcrystalline cellulose by weight of the composition; 
 vi. about 0.45% fumed silica by weight of the composition; and 
 vii. about 0.67% magnesium stearate by weight of the composition; 
 
 b) the active coating is absent; and 
 c) the film coating comprises a polymer, plasticizer and pigment. 
 
     
     
       5. The pharmaceutical composition of  claim 4 , wherein the film coating comprises hypromellose, polyethylene glycol, and optionally, one or more of polydextrose, talc, a pigment, and titanium dioxide, the pharmaceutical composition comprises the film coating in an amount of about 2.91% by weight of the composition, and the total weight of the tablet is about 240 mg. 
     
     
       6. The pharmaceutical composition of  claim 1 , wherein the active coating further comprises a polyvinyl alcohol—polyethylene glycol copolymer, wherein the polyvinyl alcohol—polyethylene glycol copolymer has an average molecular weight of about 45,000 daltons, and comprises about 75% polyvinyl alcohol units and about 25% polyethylene glycol units by weight, and the active coating and film coating each independently optionally further comprise a flavoring agent, cooling agent, sweetener, or salivation agent. 
     
     
       7. The pharmaceutical composition of  claim 1 , wherein the tablet has a mass of from about 200 mg to about 326 mg, a volume of from about 0.0106 in 3  to about 0.0183 in 3 , a surface area of from about 0.252 in 2  to about 0.395 in 2 , and a surface area to volume ratio of from about 19.4 in −1  to about 23.9 in −1 . 
     
     
       8. The pharmaceutical composition of  claim 7 , wherein the tablet has a mass selected from about 213 mg, about 214 mg, about 215 mg, about 217 mg, about 218 mg, about 219 mg, about 225 mg, about 233 mg, about 240 mg, and about 326 mg. 
     
     
       9. The pharmaceutical composition of  claim 1 , wherein the tablet has a mass of from about 110 mg to about 172 mg, a volume of from about 0.0063 in 3  to about 0.0088 in 3 , a surface area of from about 0.194 in 2  to about 0.229 in 2 , and a surface area to volume ratio of from about 26.2 in −1  to about 31.0 in −1 . 
     
     
       10. The pharmaceutical composition of  claim 9 , wherein the tablet has a mass selected from about 120 mg, about 172 mg and about 240 mg. 
     
     
       11. The pharmaceutical composition of  claim 1 , wherein the total amount of dextromethorphan or a pharmaceutically acceptable salt thereof is about 30 mg or about 60 mg. 
     
     
       12. The sustained release pharmaceutical tablet composition according to  claim 1 
 wherein the dextromethorphan or a pharmaceutically acceptable salt thereof is released from the tablet, when the tablet is stirred at 75 rpm, in 900 mL of 0.1 N HCl, and at 37° C.±0.5° C., at
 i. less than 40% in 30 minutes; 
 ii. between 15 and 60% in 1 hour; 
 iii. between 25 and 75% in 2 hours; 
 iv. between 40 and 90% in 4 hours; and 
 v. more than 70% in 8 hours. 
 
 
     
     
       13. A method of treating cough in a patient in need thereof, comprising administering to a patient in need thereof a pharmaceutical composition according to  claim 1 .